Receptor Tyrosine Kinase Signaling in Vasculogenesis and Angiogenesis

Abstract

The formation of the vascular system is an important process during embryonic development and several pathological situations. Knowledge of the molecular mechanisms may lead to the development of therapies for pathological processes involving both endothelial cell proliferation and new blood vessel formation as well as those characterized by insufficient nutrient and oxygen supply of tissues. An example for abnormal vessel growth are solid tumors, whose unlimited growth is absolutely dependent on the formation of new vessels. The tumor vasculature allows for nutrient supply and the formation of metastases [1]. Of similar negative influence is vessel growth in several non neoplastic conditions like rheumathoid arthritis, diabetic retinopathy and psoriasis [2,3]. In contrast, the growth of new vessels during collateral formation in the ischemic limb or the ischemic heart would be highly desirable [4,5]. The formation of the vascular system starts early in embryonic development with the generation of a primitive vascular plexus in the yolk sac by a process termed vasculogenesis [6]. It describes the fusion of endothelial cell precursors called angioblasts that have differentiated from mesodermal cells. While most organs of endodermal origin like the lung are vascularized by vasculogenesis, tissues of mesodermal and ectodermal origin like the kidney and brain are thought to be vascularized mostly by a different process called angiogenesis [7]. Angiogenesis is the generation of new vessels by budding and sprouting from already formed vessels or by subdivision of larger vessels (also called non-sprouting angiogenesis or intussusception). The newly formed vascular system is then reorganized by complex and poorly understood processes according to the tissue requirements. Tissue oxygen as well as glucose concentration are important regulators as low tissue levels induce the expression of factors that can induce vessel growth. The reorganization includes not only the formation of additional vessels but also the removal of excessive vessels, called pruning. The mediators of vessel regression are not known. Also, there is no direct evidence for programmed cell death (apoptosis) of endothelial cells during embryonic development. This may reflect either the limitations of the methodology applied or the rapid disappearance of apoptotic cells [8]. However, at least during certain phases endothelial cells seem to be dependent on survival factors [9].